Aurora kinases and protein phosphatase 1 mediate chromosome congression through regulation of CENP-E.

Opposing roles of Aurora kinases and protein phosphatase 1 (PP1) during mitosis have long been suggested. Here, we demonstrate that Aurora kinases A and B phosphorylate a conserved residue on the kinetochore motor CENP-E. PP1 binds CENP-E via a motif overlapping this phosphorylation site and binding is disrupted by Aurora phosphorylation. Phosphorylation of CENP-E by the Auroras is enriched at spindle poles, disrupting binding of PP1 and reducing CENP-E's affinity for individual microtubules. This phosphorylation is required for CENP-E-mediated towing of initially polar chromosomes toward the cell center. Kinetochores on such chromosomes cannot make subsequent stable attachment to spindle microtubules when dephosphorylation of CENP-E or rebinding of PP1 to CENP-E is blocked. Thus, an Aurora/PP1 phosphorylation switch modulates CENP-E motor activity as an essential feature of chromosome congression from poles and localized PP1 delivery by CENP-E to the outer kinetochore is necessary for stable microtubule capture by those chromosomes.

Robust designation of meiotic crossover sites by CDK-2 through phosphorylation of the MutSγ complex.

Crossover formation is essential for proper segregation of homologous chromosomes during meiosis. Here, we show that Caenorhabditis elegans cyclin-dependent kinase 2 (CDK-2) partners with cyclin-like protein COSA-1 to promote crossover formation by promoting conversion of meiotic double-strand breaks into crossover­specific recombination intermediates. Further, we identify MutSγ component MSH-5 as a CDK-2 phosphorylation target. MSH-5 has a disordered C-terminal tail that contains 13 potential CDK phosphosites and is required to concentrate crossover­promoting proteins at recombination sites. Phosphorylation of the MSH-5 tail appears dispensable in a wild-type background, but when MutSγ activity is partially compromised, crossover formation and retention of COSA-1 at recombination sites are exquisitely sensitive to phosphosite loss. Our data support a model in which robustness of crossover designation reflects a positive feedback mechanism involving CDK-2­mediated phosphorylation and scaffold-like properties of the MSH5 C-terminal tail, features that combine to promote full recruitment and activity of crossover­promoting complexes.

The association of dietary total flavonoids and their subclasses with the risk of type 2 diabetes: a prospective cohort study.

BACKGROUND: Data from mechanistic studies suggest flavonoids may benefit glucose metabolism, but their associations with type 2 diabetes (T2D) remain unclear. This study examined the prospective associations of dietary intake of total, classes, and individual flavonoids, as well as their source foods, with T2D in the CArdioVascular disease Association Study (CAVAS). METHODS: A total of 16,666 Korean men and women were enrolled at baseline, and 953 were newly diagnosed with T2D over a median follow-up of 5.96 years. Intake of flavonoids was cumulatively averaged using all food frequency questionnaires before the censoring events. A Poisson regression model was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). RESULTS: Women with higher total flavonoid, flavonol, isoflavone, and proanthocyanidin intake had a lower risk of T2D (fourth vs. first quartile, IRR 0.62; 95% CI 0.44-0.89; P for linearity and non-linearity < 0.05 for total flavonoids), while in men, flavanones, anthocyanins, and proanthocyanidins, but not total flavonoids, were inversely associated with T2D risk (all P interaction for sex > 0.05). The key source foods contributing to flavonoid intake were also different between men and women, except for apples: tangerines and strawberries in men and green leafy vegetables and soy products in women. CONCLUSIONS: A higher intake of total flavonoids, particularly from vegetables, soybeans, and apples, may be associated with lower risk of T2D in women. However, flavonoids from fruits, rather than total flavonoids, may be inversely associated in men. The association between flavonoid intake and the risk of T2D may be contingent upon the dietary sources of flavonoids consumed.

Habitual intake of iron, copper, and zinc and the risk of type 2 diabetes in a prospective cohort: The CAVAS (Cardiovascular Disease Association Study).

BACKGROUND AND AIMS: Unlike iron, evidence of the association between dietary copper and zinc intake and type 2 diabetes (T2D) risk is limited. This study aimed to examine the prospective associations of dietary intake of iron (total, plant-based, and animal-based), copper, and zinc with T2D risk among adults aged ≥40 years. METHODS AND RESULTS: For 16,666 participants, dietary intakes (baseline, cumulative average, and most recent) of iron, copper, and zinc were calculated from repeated food frequency questionnaires; a modified Poisson regression model with a robust error estimator was conducted. In men, positive associations between T2D and baseline dietary intake of Cu and Zn, cumulative average dietary intake of Fe (total and animal-based), Cu and Zn, and most recent dietary intake of Fe (total, plant-based, and animal-based), Cu, and Zn [most recent diet: for total Fe, IRR(95%CI) = 1.93 (1.41-2.64); for plant-based Fe, 1.56 (1.15-2.11); for animal-based Fe, 1.44 (1.09-1.90); for Cu, 3.17 (2.33-4.30); for Zn, 2.18 (1.64-2.89)] were observed, where as in women, there were positive associations of only cumulative average dietary Zn intake and most recent dietary intake of plant-based Fe, Cu, and Zn [most recent diet: for plant-based Fe, 1.30 (1.01-1.68); for Cu, 1.62 (1.27-2.08); for Zn, 2.07 (1.61-2.66)]. CONCLUSION: Dietary intakes of iron (total, plant-based, and animal-based), copper, and zinc may be positively associated with T2D risk. These positive associations are predominantly observed in most recent diet and appear to be stronger compared to baseline and cumulative average diet.

Mycobacterium potentiates protection from colorectal cancer by gut microbial alterations.

Not only are many Mycobacteria pathogens, but they can act as strong non-specific immunopotentiators, generating beneficial effects on the pathogenesis of some diseases. However, there has been no direct evidence of the effect of mycobacterial species on colorectal cancer (CRC). Herein, we showed that there may be a meaningful inverse correlation between the incidence of tuberculosis and CRC based on global statistics and that heat-killed Mycobacterial tuberculosis and live Mycobacterium bovis (Bacillus Calmette-Guérin strain) could ameliorate CRC development. In particular, using a faecal microbiota transplantation and a comparison between separate housing and cohousing, we demonstrated that the gut microbiota is involved in the protective effects. The microbial alterations can be elucidated by the modulation of antimicrobial activities including those of the Reg3 family genes. Furthermore, interleukin-22 production by T helper cells contributed to the anti-inflammatory activity of Mycobacteria. Our results revealed a novel role of Mycobacteria involving gut microbial alterations in dampening inflammation-associated CRC and an immunological mechanism underlying the interaction between microbes and host immunity.

Diagnostic accuracy of a three-protein signature in women with suspicious breast lesions: a multicenter prospective trial.

BACKGROUND: Mammography screening has been proven to detect breast cancer at an early stage and reduce mortality; however, it has low accuracy in young women or women with dense breasts. Blood-based diagnostic tools may overcome the limitations of mammography. This study assessed the diagnostic performance of a three-protein signature in patients with suspicious breast lesions. FINDINGS: This trial (MAST; KCT0004847) was a prospective multicenter observational trial. Three-protein signature values were obtained using serum and plasma from women with suspicious lesions for breast malignancy before tumor biopsy. Additionally, blood samples from women who underwent clear or benign mammography were collected for the assays. Among 642 participants, the sensitivity, specificity, and overall accuracy values of the three-protein signature were 74.4%, 66.9%, and 70.6%, respectively, and the concordance index was 0.698 (95% CI 0.656, 0.739). The diagnostic performance was not affected by the demographic features, clinicopathologic characteristics, and co-morbidities of the participants. CONCLUSIONS: The present trial showed an accuracy of 70.6% for the three-protein signature. Considering the value of blood-based biomarkers for the early detection of breast malignancies, further evaluation of this proteomic assay is warranted in larger, population-level trials. This Multi-protein Assessment using Serum to deTermine breast lesion malignancy (MAST) was registered at the Clinical Research Information Service of Korea with the identification number of KCT0004847 ( https://cris.nih.go.kr ).

Comparison of Proportional Mortality Between Korean Atomic Bomb Survivors and the General Population During 1992-2019.

BACKGROUND: Atomic bombs dropped on Hiroshima and Nagasaki in Japan in August 1945 were estimated to have killed approximately 70,000 Koreans. In Japan, studies on the health status and mortality of atomic bomb survivors compared with the non-exposed population have been conducted. However, there have been no studies related to the mortality of Korean atomic bomb survivors. Therefore, we aimed to study the cause of death of atomic bomb survivors compared to that of the general population. METHODS: Of 2,299 atomic bomb survivors registered with the Korean Red Cross, 2,176 were included in the study. In the general population, the number of deaths by age group was calculated from 1992 to 2019, and 6,377,781 individuals were assessed. Causes of death were categorized according to the Korean Standard Classification of Diseases. To compare the proportional mortality between the two groups, the P value for the ratio test was confirmed, and the Cochran-Armitage trend test and χ² test were performed to determine the cause of death according to the distance from the hypocenter. RESULTS: Diseases of the circulatory system were the most common cause of death (25.4%), followed by neoplasms (25.1%) and diseases of the respiratory system (10.6%) in atomic bomb survivors who died between 1992 and 2019. The proportional mortality associated with respiratory diseases, nervous system diseases, and other diseases among atomic bomb survivors was higher than that of the general population. Of the dead people between 1992 and 2019, the age at death of survivors who were exposed at a close distance was younger than those who were exposed at a greater distance. CONCLUSION: Overall, proportional mortality of respiratory diseases and nervous system diseases was high in atomic bomb survivors, compared with the general population. Further studies on the health status of Korean atomic bomb survivors are needed.

Diagnostic performance improvement with combined use of proteomics biomarker assay and breast ultrasound.

PURPOSE: To investigate the combined use of blood-based 3-protein signature and breast ultrasound (US) for validating US-detected lesions. METHODS: From July 2011 to April 2020, women who underwent whole-breast US within at least 6 months from sampling period were retrospectively included. Blood-based 3-protein signature (Mastocheck®) value and US findings were evaluated. Following outcome measures were compared between US alone and the combination of Mastocheck® value with US: sensitivity, specificity, positive predictive value (PPV), negative predictive value, area under the receiver operating characteristic curve (AUC), and biopsy rate. RESULTS: Among the 237 women included, 59 (24.9%) were healthy individuals and 178 (75.1%) cancer patients. Mean size of cancers was 1.2 ± 0.8 cm. Median value of Mastocheck® was significantly different between nonmalignant (- 0.24, interquartile range [IQR] - 0.48, - 0.03) and malignant lesions (0.55, IQR - 0.03, 1.42) (P < .001). Utilizing Mastocheck® value with US increased the AUC from 0.67 (95% confidence interval [CI] 0.61, 0.73) to 0.81 (95% CI 0.75, 0.88; P < .001), and specificity from 35.6 (95% CI 23.4, 47.8) to 64.4% (95% CI 52.2, 76.6; P < .001) without loss in sensitivity. PPV was increased from 82.2 (95% CI 77.1, 87.3) to 89.3% (95% CI 85.0, 93.6; P < .001), and biopsy rate was significantly decreased from 79.3 (188/237) to 72.1% (171/237) (P < .001). Consistent improvements in specificity, PPV, and AUC were observed in asymptomatic women, in women with dense breast, and in those with normal/benign mammographic findings. CONCLUSION: Mastocheck® is an effective tool that can be used with US to improve diagnostic specificity and reduce false-positive findings and unnecessary biopsies.

Effects of App-Based Mobile Interventions for Dementia Family Caregivers: A Systematic Review and Meta-Analysis.

BACKGROUND: Dementia was caregivers experience tremendous difficulties both physically and psychologically, leading to high levels of depression and caregiver burden. The advantage of mobile interventions has been recognized due to its freedom from time and space restrictions. OBJECTIVES: A systematic review and meta-analysis was conducted to evaluate effectiveness of app-based mobile interventions for dementia caregivers. METHOD: We searched nine different databases including CINAHL, the Cochrane Library, Embase, MEDLINE, PsycINFO, the ACM digital library, IEEE Xplore, KoreaMed, and RISS for publications on app-based mobile interventions targeting dementia caregivers published in English or Korean. Meta-analysis was conducted using Comprehensive Meta-Analysis (CMA) version 3.0. Standard mean difference (SMD) was used to estimate the effectiveness of the intervention on caregiver-related outcomes of caregiver burden, depression, stress, caregiving competency, and quality of life (QoL). RESULTS: Five studies (three randomized controlled trials and two quasi-experimental studies) with a total of 230 participants were included. Using a mobile device, interventions were used to provide information and feedback, perform monitoring, and conduct skill training. Pooled analysis showed favorable effects of app-based mobile interventions for caregivers on caregiver burden (SMD = -0.315, 95% CI: -0.681 to 0.052), depression (SMD = -0.236, 95% CI: -0.517 to 0.046), stress (SMD = -0.295, 95% CI: -0.708 to 0.118), competency (SMD = 0.434, 95% CI: 0.093-0.775), and QoL (SMD = 0.794, 95% CI: 0.310-1.278). CONCLUSION: Types of mobile devices, lengths, and contents of interventions varied between included studies. Given that only five studies were included, the current meta-analysis could not confirm the effectiveness of app-based mobile interventions. However, this study suggests that app-based mobile interventions for dementia caregivers might have positive effects on diverse caregiving-related issues such as caregiver burden, depression, stress, competency, and QoL.

A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles.

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.

Cumulative average nut consumption in relation to lower incidence of hypertension: a prospective cohort study of 10,347 adults.

PURPOSE: Maintaining optimal blood pressure (BP) levels can be an effective preventive strategy for reducing disease burden. Nut consumption may play a preventive role against hypertension, which is a lifelong condition. We aimed to prospectively examine the association between cumulative average nut consumption and the incidence of hypertension in Korean adults aged 40 years and older. METHODS: A total of 10,347 participants who were free of hypertension at baseline, were included. Hypertension was defined as having a physician diagnosis and taking antihypertensive medications or having abnormal BP (systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg). As an exposure, cumulative average nut consumption was calculated using repeated food-frequency questionnaires (mean: 2.1). We used a modified Poisson regression model with a robust error estimator to estimate the incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for hypertension. RESULTS: We identified 2047 incident cases of hypertension during 44,614 person-years of follow-up. Among both men and women, an average nut consumption of ≥ 1 serving/week (15 g/week]) was inversely associated with hypertension incidence (IRR = 0.74, 95% CI = 0.58-0.96, p for trend = 0.013 for men; IRR = 0.72, 95% CI = 0.59-0.88, p for trend = 0.002 for women) and these significant associations were consistently observed across the strata of potential confounders. CONCLUSION: An average consumption of at least one serving (15 g) per week of peanuts, almonds, and/or pine nuts may be inversely associated with the risk of hypertension among Korean adults aged 40 years and older, in a dose-response manner.

Genome-wide gene and serum ferritin interaction in the development of type 2 diabetes in adults aged 40 years or older.

BACKGROUND AND AIMS: Elevated serum ferritin is associated with incident Type 2 diabetes (T2D), but the interactions between serum ferritin and genetic factors which may improve understanding underlying mechanism in the development of T2D are still unclear. We determined the gene-ferritin interactions on the development of T2D by genome-wide gene-ferritin interaction analyses. METHODS AND RESULTS: A total of 3405 participants from two prospective cohorts of community living residents were included, and the median follow-time was 3.99 years. Genome-wide gene-ferritin interactions were analyzed using the joint test with two degrees of freedom and the interaction test with one degree of freedom. There were 18 SNPs selected in the joint test. Finally, four independent variants [rs355140 (LINC00312), rs4075576 (nearby PDGFA), rs1332202 (PTPRD), and rs713157 (nearby LINC00900)] with low pairwise linkage disequilibrium (r2<0.2) and located at least 1000 kb from the index SNP showed interactions with serum ferritin level. In the association analyses between serum ferritin levels (tertiles of ferritin and ferritin status) and the incidence of T2D according to genotype, the Incidence Rate Ratios (IRRs) in the highest tertile of ferritin level (vs. the lowest tertile) were greater for participants with heterozygotes of risk alleles of each of the four SNP than IRRs for those with wild type. Compared with the normal group, the elevated ferritin group also had a higher risk of T2D for all genetic variants of risk alleles, particularly its homozygotes. CONCLUSION: Serum ferritin level interacts with genetic variants (rs355140, rs4075576, rs1332202, and rs713157) in the development of T2D.

Pregnancy loss and Income in the Republic of Korea using National Health Insurance Service Data, 2008-2014.

BACKGROUND: Although unintentional pregnancy loss is common, national representative statistics are lacking in high-income East Asian countries undergoing rapid demographic changes. It is necessary to confirm the income inequality of pregnancy loss even in universal national health insurance. METHOD: Using National Health Insurance Service data between 2008 and 2014, the annual prevalence of pregnancy loss was enumerated, and differences in pregnancy loss according to age and income levels were assessed by multivariable Poisson regression. Joint-point regression was used to examine the trend of pregnancy loss. RESULT: On average, there was a 15.0% annual pregnancy loss among 3,941,020 pregnancy cases from 2008 to 2014. Pregnancy loss inequality increased stepwise with income levels except for the highest income group. After adjusting for income levels, the annual percent change of age-standardized prevalence significantly increased by 2.6% every year since 2011. CONCLUSION: Even in high-income countries with universal national health insurance, income inequality in pregnancy loss is observed. Further appraisal is needed to explain the increasing trend of pregnancy loss between 2011 and 2014 even after adjusting income.

Prevalence and risk factors of maternal depression among women who participated in a home visitation program in South Korea.

PURPOSE: The psychosocial health of mother is crucial for healthy prenatal period and early childhood. We investigated the prevalence and risk factors of maternal depression during pregnancy and postpartum among women who participated in a home visitation program in Seoul, South Korea (Seoul Healthy First Step Project, SHFSP). METHODS: We analyzed 80,116 women who participated in the SHFSP, which was launched by Seoul metropolitan government in 2013, and defined peripartum depression as a score ≥ 10 on the Korean version of the Edinburgh Postnatal Depression Scale (EPDS). Sociodemographic factors and psychosocial health status were evaluated through a standardized questionnaire completed by participants upon program registration. We calculated the prevalence of women at risk for peripartum depression and evaluated associated factors by multivariable logistic regression analysis. RESULTS: Prevalence of women at risk for peripartum depression was 17.7% (prepartum depression: 14.2%, postpartum depression: 24.3%). Younger maternal age, low income (OR 2.40, 95% CI 2.03-2.84), disability (2.61, 1.96-3.47), single parenthood (3.27, 2.69-3.99), and smoking (2.02, 1.44-2.83) increased the peripartum depression risk. Furthermore, experience of stress, change, or loss over the past 12 months (3.36, 3.22-3.50), history of treatment for emotional issues (2.47, 2.27-2.70), experience of child abuse (1.91, 1.74-2.11), and domestic violence (2.25, 1.81-2.80) increased the risk for peripartum depression, whereas having helpers for the baby (0.62, 0.58-0.67), having someone to talk with (0.31, 0.27-0.35), and considering oneself confident (0.30, 0.29-0.31) decreased the risk. CONCLUSIONS: Policies to reduce and manage peripartum depression should be strengthened, with a focus on high-risk pregnant and puerperal women.

Neighbor-Aware Non-Orthogonal Multiple Access Scheme for Energy Harvesting Internet of Things.

In a non-orthogonal multiple access (NOMA) environment, an Internet of Things (IoT) device achieves a high data rate by increasing its transmission power. However, excessively high transmission power can cause an energy outage of an IoT device and have a detrimental effect on the signal-to-interference-plus-noise ratio of neighbor IoT devices. In this paper, we propose a neighbor-aware NOMA scheme (NA-NOMA) where each IoT device determines whether to transmit data to the base station and the transmission power at each time epoch in a distributed manner with the consideration of its energy level and other devices' transmission powers. To maximize the aggregated data rate of IoT devices while keeping an acceptable average energy outage probability, a constrained stochastic game model is formulated, and the solution of the model is obtained using a best response dynamics-based algorithm. Evaluation results show that NA-NOMA can increase the average data rate up to 22% compared with a probability-based scheme while providing a sufficiently low energy outage probability (e.g., 0.05).

Different associations of specific non-alcoholic beverages with elevated high-sensitivity C-reactive protein in Korean adults: results from the Korea National Health and Nutrition Examination Survey (2015-2016).

This study examined the associations between specific non-alcoholic beverages and high-sensitivity C-reactive protein (hs-CRP) and their interactions with obesity. The study participants were 4,999 adults aged 19-64 years from the 2015-2016 Korean National Health and Nutrition Examination Survey. The odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable logistic regression analyses. In women, there was an inverse linear trend between coffee and hs-CRP status (p trend = 0.0137), and a positive linear trend for soda was also found (≥1/week vs never or almost never, OR = 1.79, 95% CI 1.23-2.61, p trend = 0.0127). In the stratification analyses, the associa-tions were only observed in obese women. The associations were inverse for coffee and tea but linearly positive for soda in obese women (p trend<0.05). In men, an inverted J-shaped association between commercial fruit juice/drink and hs-CRP status was found; but after stratification by obesity, the association was linear only in obese men (p trend<0.05, OR = 2.44, 95% CI 1.44-4.16 in ≥1/week vs never or almost never). Coffee and tea in women may be beneficially associated with hs-CRP status, but soda in women and commercial fruit juice/drink in men may be adversely, particularly for obese adults.

Mast cell tryptase-PAR2 pathway in proliferation of prostatic stromal cells reacted with Trichomonas vaginalis.

We investigated whether tryptase released from mast cells activated by prostate stromal cells (PSC) reacted with Trichomonas vaginalis (Tv) promoted the proliferation of PSC through protease- activated receptor 2 (PAR2). Conditioned medium of PSC was prepared by stimulating them with Tv (Trichomonad-conditioned medium (TCM)), and mast cell-conditioned medium were prepared by incubating them with TCM (mast cell-TCM (M-TCM)). Mast cells incubated with TCM migrated more efficiently and produced more ß-hexosaminidase and tryptase. M-TCM containing tryptase increased the proliferation of PSC, while inhibition of tryptase decreased proliferation. Expression of signalling molecules such as PAR2, p-ERK, COX-2, 15d-PGJ2 and PPARγ, known to be involved in the tryptase-PAR2 pathway, increased in response to M-TCM, and blocking any of these signals decreased proliferation, indicating that tryptase-PAR2 signalling is involved in the proliferation of PSC. Inhibition of tryptase and PAR2 led to reduced expression of PAR2, p-ERK, COX-2, 15d-PGJ2 and PPARγ, while inhibition of ERK or COX-2 reduced the expression of COX-2, 15d-PGJ2 and PPARγ indicating that the tryptase-PAR2 pathway proceeds in the order p-ERK, COX-2, 15d-PGJ2 , and PPARγ. These results show that interaction between PSC stimulated with Tv and mast cells causes proliferation of PSC through the tryptase-PAR2 pathway.

Leisure-time physical activity interventions for children and adults with cerebral palsy: a scoping review.

AIM: To summarize current evidence on the effects and reach of leisure-time physical activity (LTPA) interventions among children and adults with cerebral palsy (CP). METHOD: Systematic searches were conducted in PubMed, CINAHL, and Google Scholar to identify randomized controlled trials (RCTs) of LTPA interventions in CP. Data from eligible studies were extracted for qualitative synthesis. RESULTS: Forty-nine studies enrolled a total of 1513 participants (mean [SD] age 13y [7y], range 5-43y; 818 males, 655 females, 40 not reported) and primarily included ambulatory children. RCTs underrepresented adults and people in Gross Motor Function Classification System (GMFCS) levels IV and V. Forty-one studies reported at least one favorable benefit from LTPA. Benefits included improvements to musculoskeletal strength, cardiorespiratory fitness, quality of life, spasticity, participation, and core aspects of physical function. Regarding reach, only 34% of people that were contacted to participate enrolled within a study. A smaller percentage of participants dropped out from intervention (8%) and follow-up periods (3%). INTERPRETATION: Study findings highlight effective interventions to improve health, fitness, and function. To enhance the reach and generalizability of LTPA trials for CP, future studies should examine how to increase study sample sizes and aim to include a better representation of adults and people in GMFCS levels IV and V. WHAT THIS PAPER ADDS: People with cerebral palsy (CP) may experience improvements in health, fitness, and physical function from leisure-time physical activity (LTPA) interventions. Effective interventions include exercise training, active video games, recreation activities, behavioral coaching, and motor skills training. Interventions that incorporate telehealth technology, behavioral coaching, and community resources may enhance LTPA. Interventions primarily include children in Gross Motor Functional Classification System (GMFCS) levels I to III. Adults, wheelchair users, and those in GMFCS levels IV and V are underrepresented.

The Osteogenic Differentiation of Human Dental Pulp Stem Cells through G0/G1 Arrest and the p-ERK/Runx-2 Pathway by Sonic Vibration.

Mechanical/physical stimulations modulate tissue metabolism, and this process involves multiple cellular mechanisms, including the secretion of growth factors and the activation of mechano-physically sensitive kinases. Cells and tissue can be modulated through specific vibration-induced changes in cell activity, which depend on the vibration frequency and occur via differential gene expression. However, there are few reports about the effects of medium-magnitude (1.12 g) sonic vibration on the osteogenic differentiation of human dental pulp stem cells (HDPSCs). In this study, we investigated whether medium-magnitude (1.12 g) sonic vibration with a frequency of 30, 45, or 100 Hz could affect the osteogenic differentiation of HDPSCs. Their cell morphology changed to a cuboidal shape at 45 Hz and 100 Hz, but the cells in the other groups were elongated. FACS analysis showed decreased CD 73, CD 90, and CD 105 expression at 45 Hz and 100 Hz. Additionally, the proportions of cells in the G0/G1 phase in the control, 30 Hz, 45 Hz, and 100 Hz groups after vibration were 60.7%, 65.9%, 68.3%, and 66.7%, respectively. The mRNA levels of osteogenic-specific markers, including osteonectin, osteocalcin, BMP-2, ALP, and Runx-2, increased at 45 and 100 Hz, and the ALP and calcium content was elevated in the vibration groups compared with those in the control. Additionally, the western blotting results showed that p-ERK, BSP, osteoprotegerin, and osteonectin proteins were upregulated at 45 Hz compared with the other groups. The vibration groups showed higher ALP and calcium content than the control. Vibration, especially at 100 Hz, increased the number of calcified nodes relative to the control group, as evidenced by von Kossa staining. Immunohistochemical staining demonstrated that type I and III collagen, osteonectin, and osteopontin were upregulated at 45 Hz and 100 Hz. These results suggest that medium magnitude vibration at 45 Hz induces the G0/G1 arrest of HDPSCs through the p-ERK/Runx-2 pathway and can serve as a potent stimulator of differentiation and extracellular matrix production.

Ophiopogonin D ameliorates DNCB-induced atopic dermatitis-like lesions in BALB/c mice and TNF-α- inflamed HaCaT cell.

Atopic dermatitis (AD) can occur in both children and adults, and the symptoms include itching and eczema, which in turn cause patients to suffer. Ophiopogonin D (OP-D) is a steroidal glycoside from Radix Ophiopogon japonicus, which is well known as an effective anti-inflammatory herbal medicine in many Asian countries. In this study, we aimed to investigate the anti-inflammatory effects of OP-D, using an AD mouse model and inflamed HaCaT cells. Through a histopathological analysis, we were able to confirm the suppressive effects of OP-D on skin thickening and the mast cell activation in AD-like mouse back skin tissues stimulated by DNCB. In addition, we detected significant decreases in cytokine expression levels through multiplex assessment assays of the OP-D-treated mice blood. We observed the anti-inflammatory effect of OP-D in the spleen, causing weight loss in the spleen and in the mRNA expression levels related to diverse cytokines. In human keratinocytes inflamed by TNF-α, OP-D inhibited p38 and ERK protein activation and showed a reduction of NF-κB nuclear translocation. Furthermore, OP-D attenuated pro-inflammatory cytokine mRNA expressions in TNF-α-inflamed HaCaT cells. Accordingly, we came to the conclusion that OP-D is a potential natural drug which can be used in order to treat inflammatory skin diseases, such as AD.